Our overall hypothesis is that oxytocin is an important contributor to neonatal cerebrovascular control especially following pharmacological and pathological impairment of the prostaglandin synthetic system. Our hypothesis is supported by several interconnecting findings in newborn pigs: 1) Oxytocin levels increase in cerebrospinal fluid (CSF) and plasma to vasoactive levels during stressful conditions such as asphyxia, increased intracranial pressure, and osmotic stress; 2) Indomethacin pretreatment reverses cerebral arteriolar responses to oxytocin from dilation to potent constriction; 3) Indomethacin pretreatment alters oxytocinergic vascular responses in both pial arterioles and basilar artery; and 4) Pathological conditions such as global ischemia and the presence of subarachnoid blood cause impairment of prostaglandin-dependent responses in the cerebral circulation. Based upon our findings and those in the literature, we propose the following specific hypotheses: 1. Cerebral resistance vessels are exposed to vasoactive levels of oxytocin via CSF and plasma; 2. Prostaglandin synthetic capabilities of cerebral tissues and/or vessels are an important determinant of cerebrovascular responses to oxytocin; and 3. Impairment of the prostaglandin system by pathological stimuli results in altered responsiveness of cerebral arteries and arterioles to oxytocin. To test these hypotheses, three specific aims will be addressed using newborn pigs: 1. CHARACTERIZATION OF OXYTOCINERGIC EFFECTS ON CEREBROVASCULAR HEMODYNAMICS; 2. INVESTIGATION OF THE CONTRIBUTION OF PROSTAGLANDINS TO CEREBROVASCULAR RESPONSES TO OXYTOCIN; and 3. DETERMINATION OF CEREBROVASCULAR EFFECTS OF OXYTOCIN FOLLOWING PATHOLOGICAL ALTERATIONS IN THE PROSTAGLANDIN SYSTEM. We will use several complimentary methods for studying cerebrovascular responses, including the closed cranial window and intravital microscopy for characterization of individual arteries and arterioles in vivo, radioactive microspheres for determination of total and regional cerebral blood flow, microvascular measurement of blood pressure for determination of segmental resistance, and in vitro approaches for examining vascular responses in isolation. In addition, we will determine oxytocin and prostaglandin levels by radioimmunoassay. This investigation will explore control mechanisms in neonatal animals during normal and pathological conditions. We hope that our findings will be of clinical relevance and lead to therapies that improve outcome in stressed babies.
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